U.S. Pat. Nos. 2,781,342, 3,444,160 and 3,655,649 all disclose processes for producing enamines of 3-keto or .DELTA..sup.4 -3-ketosteroids by use of secondary amines including piperidine and morpholine.
U.S. Pat. No. 3,192,201 claims the 3,22-dienamine (piperidine) of "pyro" bisnoraldehyde. Example 2A discloses "pyro" bisnoraldehyde-22-piperidine enamine.
U.S. Pat. No. 2,752,368 and M. E. Herr and F. W. Heyl in J. Am. Chem. Soc. 74, 3627 (1952) disclose processes to prepare the piperidine and morpholine 22-enamines of bisnoraldehyde. Both items disclose the reaction of bisnoraldehyde and an excess of piperidine in benzene under reflux accompanied by azeotropic removal of water to give the desired bisnoraldehyde-22-enamine product. The morpholine analog was prepared in the same way using an excess of morpholine in toluene.
In the above references the ketone or aldehyde is reacted with an amine to produce the desired enamine with expected splitting out of water. In order to drive the equilibrium in the desired direction the water is removed in the usual manner by azeotropic distillation leaving the desired product. The process of the present invention does not necessitate or require the removal of the water because the process of enamine exchange does not produce water and the product precipitates out and can be recovered in very high purity.
Acid catalysts were disclosed in U.S. Pat. Nos. 2,781,342 and 3,444,160 and inert solvents (substituted amides) were disclosed in U.S. Pat. No. 3,444,160.
U.S. Pat. No. 3,661,942 issued in 1972 claiming a very simple process of oxidative cleavage of an enamine (bisnoraldehyde-22-enamine) to a ketone (progesterone) by use of oxygen and a copper catalyst. In particular, see claim 4. However, in order to take advantage of this copper catalyzed oxidative cleavage the enamine starting material must be quite pure. The prior art processes, cited above, for production of bisnoraldehyde-22-enamine (III) do not in a simple manner produce material of sufficient purity in high yield to be able to utilize directly and efficiently the process of U.S. Pat. No. 3,661,942. The bisnoraldehyde-22-enamine (III) produced by the process of the present invention is sufficiently pure to permit use of the process of U.S. Pat. No. 3,661,942 to convert it to progesterone.